Phase I/Ib Dose-escalation of Dinaciclib With Weekly Paclitaxel for Advanced Solid Tumor Malignancies & Assessment of MYC Oncogene Overexpression

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Jo Chien, University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT01676753
First received: August 24, 2012
Last updated: March 24, 2014
Last verified: March 2014
  Purpose

The purpose of this trial is to collect safety data for the combination of weekly paclitaxel and dinaciclib in patients with advanced solid tumor malignancies. After the Phase 2 dose is determined, a 12 subject expansion cohort in patients with advanced triple negative breast cancer will be opened.


Condition Intervention Phase
Malignant Solid Tumour
Triple-negative Breast Cancer
Drug: Dinaciclib & paclitaxel treatment
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/Ib Dose-escalation Trial of the Cyclin-dependent Kinase Inhibitor Dinaciclib in Combination With Weekly Paclitaxel in Patients With Advanced Solid Tumor Malignancies and Assessment of MYC Oncogene Overexpression

Resource links provided by NLM:


Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • Maximum tolerated dose (MTD) [ Time Frame: Measured during Cycle 1 (28 Days) for each cohort, up to 3 cohorts (about 3 months) ] [ Designated as safety issue: Yes ]
    The MTD is measured (safety/tolerability) by clinical review of relevant AE parameters (i.e. laboratory tests, physical exams)

  • Define dose-limiting toxicities (DLTs) [ Time Frame: Up to 8 Cycles (approx 8 months) ] [ Designated as safety issue: Yes ]
    Toxicities will be graded in severity per CTCAE version 4.0, based on events occurring during the first Cycle for each cohort


Secondary Outcome Measures:
  • Anti-tumor activity in patients with advanced triple negative breast cancer [ Time Frame: Up to 8 Cycles (approx 8 months) ] [ Designated as safety issue: No ]
    Response and progression will be evaluated using RECIST 1.1 criteria based on radiographic studies performed every 8 weeks

  • Impact of paclitaxel on pharmacokinetics of dinaciclib [ Time Frame: Up to 8 Cycles (approx 8 months) ] [ Designated as safety issue: No ]
    Plasma dinaciclib concentration-time data will be p taken (blood draws) pre-dose to post-dose (0-12 hr) to determine PK parameters (Cmax, Tmax, AUC)

  • Biomarkers-dinaciclib activity [ Time Frame: Baseline to pre-Cycle 3 (approximately 3 months) ] [ Designated as safety issue: No ]
    Biopsy tissue will be assesed at baseline/pre-treatment and pre-Cycle 3, to correlate the biomarkers relevant to dinaciclib activity and MYC expression with clinical response


Estimated Enrollment: 30
Study Start Date: August 2012
Estimated Study Completion Date: August 2016
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dinaciclib & paclitaxel treatment
Weekly dinaciclib in combination with weekly paclitaxel
Drug: Dinaciclib & paclitaxel treatment
Weekly dinaciclib in combination with weekly paclitaxel
Other Name: Single Arm

Detailed Description:

This is a single-site, open-label phase I/Ib trial of weekly dinaciclib in combination with weekly paclitaxel in patients with advanced solid tumor malignancies. Any number of prior therapies is allowed. Prior treatment with paclitaxel is allowed. Paclitaxel will be administered weekly by 1-hour intravenous infusion at a fixed dose of 80 mg/m2 during a 28-day repeating cycle. Dinaciclib will be administered weekly by 2-hour intravenous infusion 24 hours later. Dinaciclib is the investigational agent and will be dose escalated using a 3+3 design. Only 2 cohorts are planned, although additional cohorts exploring intermediate doses or specific patient subsets may be added. The starting dinaciclib dose is 7 mg/m2. The primary objective is to define the maximum tolerated dose of dinaciclib when given weekly in this combination and schedule. The primary endpoint is safety and tolerability. Secondary objectives include evaluation of the preliminary efficacy of this combination and determination of pharmacokinetic interactions between dinaciclib and paclitaxel. Exploratory studies characterizing and correlating the biomarkers relevant to dinaciclib activity and MYC overexpression with clinical response will be performed.

  Eligibility

Ages Eligible for Study:   18 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

INCLUSION CRITERIA:

Dose escalation cohorts

  1. Histologically or cytologically documented, incurable, unresectable locally advanced, or metastatic solid tumor malignancy
  2. The tumor biopsy is optional in the dose-finding phase of the protocol
  3. Patient is male or female and ≥ 18 years of age on the day of signing informed consent.
  4. Patient must have performance status of 0-2 on the ECOG Performance Scale and life expectancy > 3 months
  5. Patient must have evaluable disease
  6. Patient must have adequate organ function as indicated by the following laboratory values:

    Hematological

    • Absolute neutrophil count (ANC) ≥ 1,500 /μL
    • Platelets ≥ 100,000 /μL
    • Hemoglobin ≥ 9 g/dL

    Renal

    • Serum creatinine or calculated creatinine clearance ≤ 1.5 x upper limit of normal (ULN) OR
    • ≥ 60 mL/min for patients with creatinine levels > 1.5 x institutional ULN

    Hepatic

    • Serum total bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 x ULN
    • AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN

    Coagulation

    • Prothrombin time (PT)/INR ≤ 1.2 x ULN
    • Partial thromboplastin time (PTT) ≤ 1.2 x ULN

    Metabolic

    • Potassium, Calcium, Phosphorus in normal range
    • Uric Acid in normal range
  7. Female patient of childbearing potential must have a negative serum or urine pregnancy test β-hCG and agree to the use of effective methods of contraception while on study.
  8. Patient has voluntarily agreed to participate by giving written informed consent
  9. Prior taxane in the adjuvant or metastatic setting is allowed
  10. Any number of prior lines of chemotherapy in the metastatic setting is allowed
  11. Concomitant use of bisphosphonates is allowed
  12. Patients with stable and clinically insignificant CNS disease are allowed, patients must be off steroids with no new CNS symptoms or findings on radiographic imaging

Dose expansion cohort

  1. Histologically documented metastatic or locally advanced unresectable breast cancer that is ER and PR ≤ 10% expression and does not over-express HER2 protein (IHC 0, 1+, or 2+and FISH < 2.0)
  2. Patient must consent to a biopsy of a site of disease unless the only site of disease is lung/pleura
  3. Patient must have measureable disease
  4. All other inclusion criteria per the dose escalation cohorts

EXCLUSION CRITERIA:

Both dose escalation and dose expansion cohorts

  1. Patient who has had radiotherapy or hormonal therapy within 2 weeks, chemotherapy within 3 weeks or 5 half-lives, whichever is shorter (6 weeks for nitrosoureas, mitomycin C or bevacizumab), or who has not recovered from toxicity due to previous agents administered. If the patient has residual toxicity from prior treatment, toxicity must be ≤ Grade 1.
  2. Patients less than 4 weeks post major surgical procedure (all surgical wounds must be fully healed). For the purpose of this criterion, a major surgical procedure is defined as one requiring the administration of general anesthesia.
  3. Patient is currently participating or has participated in a study with an investigational compound or device within 30 days of Study Day 1
  4. Patient has known active CNS metastases and/or carcinomatous meningitis. However, patients with CNS metastases who have completed a course of therapy would be eligible for the study provided they are clinically stable for at least 1 month prior to entry as defined as: (1) no evidence of new or enlarging CNS metastasis (2) off steroids. Patients with clinically insignificant brain metastases that do not require treatment are eligible.
  5. Patient has a primary central nervous system tumor
  6. Patient has known hypersensitivity to the components of study drug or its analogs. Patients who have had a hypersensitivity reaction to paclitaxel or products formulated with Cremophor® EL (polyoxyethylated castor oil) should not be enrolled in this study.
  7. Patient has a history or current evidence of clinically significant heart disease including:

    • Clinically significant congestive heart failure, unstable angina pectoris
    • Clinically significant cardiac arrhythmia Myocardial infarction during the last 6 months, and/or a current ECG tracing that is abnormal in the opinion of the treating Investigator QTc prolongation > 450 msec (Bazett's Formula)
    • Congenitally long QT syndrome, and/or current anti-arrhythmic therapy, has received any marketed or experimental compound in the last 4 weeks prior to entering the study with possible or known effects of QT prolongation, or cumulative high-dose anthracycline therapy.
  8. Patient with evidence of clinically significant bradycardia (HR < 50), or a history of clinically significant bradyarrhythmias such as sick sinus syndrome, 2nd degree AV block (Mobitz Type 2), Patient with uncontrolled hypertension (≥ 140/90 mmHg). Patients who are controlled on antihypertensive medication will be allowed to enter the study.
  9. Patient has a history or current evidence of any condition, therapy, or lab abnormality that might confound the results of the study, interfere with the patient‟s participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
  10. Patient has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  11. Patient is, at the time of signing informed consent, a regular user of any illicit drugs or had a recent history (within the last year) of drug or alcohol abuse.
  12. Patient is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study
  13. Patient is known to be Human Immunodeficiency Virus (HIV)-positive
  14. Patient has known history of active Hepatitis A, B, or C
  15. Patient has symptomatic ascites or pleural effusion, a patient who is clinically stable following treatment for these conditions is eligible
  16. Patient is receiving treatment with oral corticosteroids (physiologic replacement doses and inhaled corticosteroids are permitted)
  17. Patient has baseline neuropathy of ≥ grade 2
  18. Patients who have known allergic reactions to paclitaxel or IV contrast dye despite standard prophylaxis
  19. Patients who require medications that are strong CYP3A4 inhibitors or inducers. Patients who have discontinued any of these medications must have a wash-out period of at least 5 days or at least 5 half-lives of the drug (whichever is longer) prior to the first dose of dinaciclib.
  20. Patients requiring warfarin therapy, low molecular weight heparin is permitted
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01676753

Locations
United States, California
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States, 94143
Sponsors and Collaborators
Jo Chien
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: A Jo Chien, MD University of California, San Francisco
  More Information

No publications provided

Responsible Party: Jo Chien, UCSF Assistant Clinical Professor, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01676753     History of Changes
Other Study ID Numbers: UCSF CC# 12951
Study First Received: August 24, 2012
Last Updated: March 24, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Paclitaxel
Cyclin-Dependent Kinase Inhibitor Proteins
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 28, 2014